调节性B细胞
癌症研究
表观遗传学
肝细胞癌
肿瘤微环境
生物
B细胞
免疫系统
白细胞介素10
免疫学
基因
抗体
生物化学
作者
Lu Zhou,Ronghua Liu,Yining Wang,Mengxia Jiao,Zhongchen Li,Zhiqiang Wang,Cheng Huang,Guo‐Ming Shi,Ai–Wu Ke,Luman Wang,Ying Fu,Jie Xia,Haoyu Wen,Jian Zhou,Xiaoying Wang,Dan Ye,Jia Fan,Yiwei Chu,Jia‐Bin Cai
出处
期刊:Hepatology
[Wiley]
日期:2023-02-17
卷期号:77 (3): 745-759
被引量:11
摘要
IL-10-producing regulatory B cells (IL-10 + B cells), a dominant regulatory B cell (Breg) subset, foster tumor progression. However, the mechanisms underlying their generation in HCC are poorly understood. Ten-eleven translocation-2 (TET2), a predominant epigenetic regulatory enzyme in B cells, regulates gene expression by catalyzing demethylation of 5-methylcytosine into 5-hydroxymethyl cytosine (5hmC). In this study, we investigated the role of TET2 in IL-10 + B cell generation in HCC and its prospects for clinical application.TET2 activation in B cells triggered by oxidative stress from the HCC microenvironment promoted IL-10 expression, whereas adoptive transfer of Tet2 -deficient B cells suppressed HCC progression. The aryl hydrocarbon receptor is required for TET2 to hydroxylate Il10 . In addition, high levels of IL-10, TET2, and 5hmc in B cells indicate poor prognosis in patients with HCC. Moreover, we determined TET2 activity using 5hmc in B cells to evaluate the efficacy of anti-programmed death 1 (anti-PD-1) therapy. Notably, TET2 inhibition in B cells facilitates antitumor immunity to improve anti-PD-1 therapy for HCC.Our findings propose a TET2-dependent epigenetic intervention targeting IL-10 + B cell generation during HCC progression and identify the inhibition of TET2 activity as a promising combination therapy with immune checkpoint inhibitors for HCC.
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